Triptolide‐induced hepatotoxicity via apoptosis and autophagy in zebrafish. Issue 11 (19th July 2019)

• Record Type: Journal Article
• Authors: Huo, Jingting; Yu, Qinwei; Zhang, Yun; Liu, Kechun; Hsiao, Chung‐Der; Jiang, Zhenzhou; Zhang, Luyong
• Is Part Of: Journal of applied toxicology. Volume 39:Issue 11(2019)
• Page Start: 1532
• Page End: 1540
• Publication Date: 2019-07-19
• Subjects: apoptosis -- autophagy -- hepatotoxicity -- high‐content imaging -- triptolide -- zebrafish; Toxicology -- Periodicals; Industrial toxicology -- Periodicals; Environmentally induced diseases -- Periodicals; Toxicology -- Periodicals; 615.9005
• DOI: 10.1002/jat.3837
• Languages: English
• ISSNs: 0260-437X

Abstract

Abstract: Previous research about the development of triptolide (TP) as a natural active compound has often focused on hepatotoxicity. Among its various mechanisms, autophagy and apoptosis are two important signaling pathways. In this study, we used zebrafish to establish a TP‐induced hepatotoxicity model, and investigated the roles of autophagy and apoptosis in the progress of liver injury. Zebrafish exposed to TP showed increased mortality and malformation because of the increased drug dose and duration of exposure. Meanwhile, we found that TP induced liver injury in a time‐ and dose‐dependent manner, which was observed as a reduction in liver area, slow yolk absorption, upregulation of transaminase and local neurosis. With the application of the high‐content imaging system (HCIS) technique in liver 3D imaging in vivo, clear imaging of the zebrafish liver was achieved. The results showed a decrease in volume and location of necrosis in the liver after TP exposure. Increased expression of inflammatory cytokines genes tumor necrosis factor ( Tnf ) α, Il1β and Il6 were shown, particularly Tnfα . The Fas‐Caspase8 signaling pathway was activated. The apoptosis‐related gene Bcl‐2 was increased, and Bax, Caspase9 and Caspase3 were increased. However, autophagy related genes Beclin1, Atg5, Atg3 and Lc3 were increased more significantly, and the changes of Beclin1 and Atg5 were the most severe. This study successfully established a TP‐induced zebrafish hepatotoxicity model and applied the HCIS technique in a zebrafish hepatotoxicity study. The result indicated Fas might be the main target of TP‐induced hepatotoxicity. Autophagy played a more important role than apoptosis and was characterized by the overexpression of Beclin1 and Atg5 . Abstract : In this study, we investigated that the mechanism of triptolide‐induced hepatotoxicity in zebrafish is based on the activation of the autophagy and apoptosis signaling pathway. It was found that the Fas ‐ Caspase8 signaling pathway was activated by triptolide; however, the upregulation of Beclin1 ‐ and Atg5 ‐induced autophagy was more significant than Bax/Bcl‐2 ‐induced apoptosis. Moreover, the high content imaging system was a novel application in the study of zebrafish hepatotoxicity.